tbuckley/cabot-search huggingface dataset:
A phase 2 study of the MDM2 inhibitor milademetan in patients with <i>TP53</i>-wild type and <i>MDM2</i>-amplified advanced or metastatic solid tumors (MANTRA-2).
Authors: Ecaterina Elena Dumbrava, Glenn J. Hanna, Gregory Michael Cote, Tom Stinchcombe, Melissa Lynne Johnson, Christopher Chen, Siddhartha Devarakonda, Naisargee Shah, Feng Xu, Robert Charles Doebele, Mrinal M. Gounder
Journal: Journal of Clinical Oncology (2022)

TPS3165 Background: Murine double minute 2 (MDM2) is a potent negative regulator of the tumor suppressor p53. MDM2 induces degradation of p53 and promotes tumorigenesis in solid tumors, and preclinical models have shown that inhibition of MDM2 can restore p53 tumor suppressor activity in TP53-wild type (WT), MDM2-amplified tumors. We performed a mutual exclusivity analysis of patients with solid tumors (n = 42,125; AACR Project GENIE) and found that the frequency of co-occurring TP53 mutations decreased with increasing MDM2 copy number. An MDM2 copy number of 12 was chosen as the threshold. An estimated 1.1% of solid tumors meet this molecular criteria, excluding glioblastomas, dedifferentiated liposarcomas, and intimal sarcomas where this signature is enriched. Milademetan (RAIN-32), an oral, selective MDM2 inhibitor, inhibits growth of TP53-WT/ MDM2-amplified cell lines and patient-derived xenograft models from varying tumor types. Furthermore, tumor regression was observed in 3/3 non-liposarcoma patients with MDM2 copy number &gt; 12 in a phase 1 trial of milademetan. MANTRA-2 (RAIN-3202) is a phase 2, multicenter, single-arm, open-label, basket trial designed to evaluate the efficacy or clinical benefit of milademetan in TP53-WT solid tumors with MDM2 amplification (copy number ≥ 12). Methods: Eligible patients must be ≥ 18 years of age with histologically and/or cytologically confirmed locally advanced, incurable or metastatic solid tumors refractory to standard therapy. Local testing demonstrating TP53 WT and MDM2 amplification is required, defined as a MDM2 copy number ≥ 12 or 6-fold increase. Patients with well-differentiated/de-differentiated liposarcomas, intimal sarcomas, or primary central nervous system tumors are excluded. Prior treatment with an MDM2 inhibitor is not permitted. Patients receive milademetan 260 mg orally once daily on Days 1–3 and 15–17 of a 28-day cycle. Tumor response is evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: objective response rate. Secondary endpoints include: duration of response; progression-free survival; growth modulation index; disease control rate; overall survival; safety; health-related quality of life scores. Exploratory endpoints include: biomarkers in blood and/or tumor tissue; pharmacodynamics; pharmacokinetics. Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥ 12. The trial opened in November 2021 and is actively enrolling patients. Clinical trial information: NCT05012397.
Real-world outcomes of niraparib treatment in patients with ovarian cancer: The first observational multicenter study in China.
Authors: Jin Li, Xiaohua Wu, Huafeng Shou, Fei Zheng, Xiaohong Huang, Fang Liu, Xuedong Tang, Jianhua Yang, Lin Zhang
Journal: Journal of Clinical Oncology (2022)

e17614 Background: Compared with western countries, the application time of PARP inhibitor in China is shorter and the real world outcomes are affected by many factors. The objective of this study was to present the real-world patients’ portrait, and the results of Niraparib treatment in China. Methods: This study included 142 patients treated with Niraparib from 8 hospitals in China between Dec. 2018 and Sep. 2021. Patients’ characteristics were summarized. The efficacy and safety in first-line maintenance (1L-M), platinum-sensitive recurrence maintenance (PSR-M), and treatment for ovarian cancer were evaluated. Survival outcomes and the factors influencing PFS were estimated. Results: 93 patients received Niraparib as 1L-M, 31 as PSR-M and 18 as salvage. BRCA status was wild-type or unknown in 87.3% of patients. With a median follow-up time of 8.7m, the mPFS for 1L-M has not yet been reached, and the mPFS for PSR-M and salvage therapy was 10.5 months (95%CI: 3.9-NE) and 5.7 months (95%CI: 3.0-13.0), respectively. Responses to last chemotherapy (CR vs. PR, P= 0.0077) and CA125 value before taking Niraparib (≤35UI/ml vs. &gt; 35UI/ml, P= 0.0344) were two important factors affecting PFS among 1L and PSR patients. 12.7%(18/142) of patients experienced grade ≥3 hematologic adverse events and 23.2% experienced dose adjustment. It was noteworthy that when the interval of chemotherapy and Niraparib &lt; 21 days, the incidence of Grade ≥ 3 adverse events increased significantly ( P= 0.0355). Conclusions: This was the first and largest observational multicenter study reporting the outcomes of Niraparib treatment for ovarian cancer in real-world setting in China. Generally, Niraparib was effective and well tolerated, which was consistent with the results of prospective trials. However, in real world, it was more inclined to use Niraparib in late-line treatment without genetic testing.
A retrospective study on the efficacy and safety of regorafenib or regorafenib combined with immune-checkpoint-inhibitors (ICIs) after first-line therapy in patients with advanced hepatocellular carcinoma.
Authors: Tao Yan, Caiyun Peng, Lingxiang Yu, Xuezhang Duan, Dong Ji, Linzhi Zhang, Jiamin Cheng, Tong Wu, Guodong Su, Yi Jing, Yinyin Li, Yinying Lu
Journal: Journal of Clinical Oncology (2022)

e16115 Background: The efficacy of first-line ICIs combination therapy patients with advanced hepatocellular carcinoma (HCC) was better than that of TKIs alone. This study was conducted to explore whether regorafenib combined with ICIs has better efficacy in second-line therapy. Methods: This retrospective study included 101 patients who have received regorafenib after the failure of at least one molecular-targeted therapy evaluated between March 2017 to November 2021. The patients were divided into two groups based on receiving regorafenib (cohort A) or regorafenib combined with ICIs(cohort B). The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), and safety. Results: 29 patients were in the cohort A and 72 were in the cohort B. There were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous therapy regimens between the two cohorts. Among them, the first-line therapy mainly includes sorafenib, lenvatinib with or without ICIs. The median PFS (4.0 months), 6 months PFS rate (25.66%) and DCR(65.52%) of cohort A were poor than that of cohort B (8.7 months, 83.33%, 74.13%), (P＜0.05). OS data was not yet available. First-line therapy, use of TKI with ICIs (n = 31) or TKI without ICIs(n = 27) (PFS 8.70m VS 8.37m，P = 0.84), use of sorafenib with or without ICIs (n = 22), or lenvatinib with or without ICIs (n = 33)(PFS 8.87m VS 7.60m，P = 0.77), didn’t affect the PFS and ORR of the later line therapeutic regimens. In the cohort B, the ORR of the second-line (29.31%) was better than that of the third-line (0), (P = 0.03). Adverse events (AEs) of all grades were statistically different between the two groups (P = 0.03), but there was no significant difference in the incidence of grade 3-4 AE. Conclusions: In the later-line therapy, regorafenib combined with ICIs therapy showed better curative effect, especially in the second-line. Regorafenib combined with ICIs is recommended as early as second-line therapy to benefit patients. Different regimens of first-line therapy have no effect on PFS in second-line therapy.[Table: see text]
MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor.
Authors: Ruben A. Mesa, Aaron Thomas Gerds, Alessandro Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew T. Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Cornelia Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal P. McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2022)

7002 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials. This pivotal phase 3 study of MF patients (pts) previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks). Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb &lt;10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm. Stratification: TSS, palpable spleen, and RBC units transfused. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks, after which pts could receive open-label MMB. Assessments: Pt reported symptoms using a daily eDiary and spleen volume by MRI or CT. The primary endpoint was TSS response (≥50% reduction from baseline [BL]) rate at wk 24. Secondary endpoints, assessed sequentially at wk 24, were RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 94 of 130 (72%) MMB pts and 38 of 65 (58%) DAN pts completed the 24-wk randomized treatment (RT) phase. Median BL TSS were 28 (MMB) and 26 (DAN), Hgb were 8.1 (MMB) and 7.9 (DAN) g/dL, and platelets were 97 (MMB) and 94 (DAN) x10 9 /L. BL TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). All primary and key secondary endpoints were met (Table). Most common Gr ≥3 TEAEs in the RT phase of the study were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). Gr ≥3 infections occurred in 15% of MMB and 17% of DAN pts. Peripheral neuropathy occurred in 5 (4%) of MMB (all Gr ≤2) and 1 (2%) of DAN (Gr ≤2) pts in the RT phase, and none discontinued study drug. Overall, TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). Conclusions: In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia. Clinical trial information: NCT04173494. [Table: see text]
Association of intrathecal trastuzumab to standard therapy in patients with leptomeningeal metastasis in HER2 positive breast cancer.
Authors: Oana Gabriela Trifanescu, Laurentia Minea Gales, Ana Ciornei, Dan Mitrea, Rodica Maricela Anghel
Journal: Journal of Clinical Oncology (2022)

e13021 Background: Leptomeningeal metastases are rare but fatal manifestation of metastatic breast cancer, especially in HER2 positive sub-type, with limited treatment options and median overall survival in the range of only 4-6 weeks in untreated patients. Methods: Our prospective study included 9 patients with HER2 positive breast cancer with leptomeningeal metastases that received intrathecal treatment with Trastuzumab along with systemic therapy. Data was compared with a control lot of 9 patients with leptomeningeal metastasis that did not receive intrathecal treatment. Radiotherapy was administered in all patients. The patients included in the study received cures of 150 mg of Trastuzumab injected intrathecal every 3 weeks. Results: Median age of the patients at the time of diagnosis was 53 years. Median time from diagnosis of BC until diagnosis of leptomeningeal carcinomatosis was 3.4 years. Median progression free survival for patients receiving trastuzumab intrathecal was 11.1 months compare with 6.4 months in patients receiving standard treatment, p &lt; 0.019. In our lot of patients, response rate was 66.6%. A clinical benefit with symptoms relief was observed in 77.7% of patients. Mean number of administrations was 12. Two patients presented pain and in two instance the administration was not possible. Concurrent systemic treatment consisted in lapatinib and capecitabine (22.2%), trastuzumab emtansine (44.5%), tucatinib combination (22.2%), vinorelbine (11.1%) and no unexpected toxicity to systemic treatment was noticed. Conclusions: Intrathecal administration of trastuzumab along with systemic treatment and radiotherapy, might improve or stabilise the consequences of leptomeningeal involvement by HER2-positive breast cancer with manageable toxicity.
Mismatched donor transplantation with post-transplantation cyclophosphamide for advanced cutaneous T-cell lymphoma: A single-center experience.
Authors: Michael Sang Hughes, Cole Harris Sterling, Ravi Varadhan, Richard F. Ambinder, Richard J. Jones, Sima Rozati, Javier Bolanos-Meade, Leo Luznik, Alexander Joseph Ambinder, Nina D. Wagner-Johnston, Ephraim Joseph Fuchs
Journal: Journal of Clinical Oncology (2022)

e19045 Background: Mismatched blood or marrow transplantation (BMT) using post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has not been well-studied in CTCL. Methods: We analyzed all patients above 18 years old with relapsed/refractory CTCL undergoing mismatched alloBMT. Primary endpoints included disease-free survival (DFS) and overall survival (OS). Secondary endpoints included time to neutrophil and platelet recovery, GvHD outcomes, and day +30 and day +60 donor chimerism. Results: From 2003-2020, 8 patients with relapsed CTCL underwent mismatched related (n=7) or mismatched unrelated (n=1) BMT. Mean age was 50 years (range 30-62); median time from diagnosis was 2 years (range 1.3-11.4). All had received prior treatment for their disease; two (25%) had received immune checkpoint inhibitors. Four (50%) were in partial response and 4 (50%) were in complete remission prior to BMT. Six received bone marrow grafts. Two received mobilized peripheral blood. Five (62.5%) achieved full donor chimerism by day 30 after BMT; 6 (75%) had achieved full donor chimerism by day 60 after BMT. One patient failed to engraft. Mean time to neutrophil recovery was 17.3 days (range 17-45); mean time to platelet recovery was 28.4 days (range 11-69). Median DFS was 11.3 months (95% confidence interval 2.6 months-not reached). Median OS was not reached. One patient developed grade 1 acute GvHD, and 2 patients developed mild chronic GvHD. There were no instances of transplantation-related mortality (TRM). At 1 year post-BMT, 4 patients had relapsed (50%), and no patients had died. At 3 years post-BMT, 7 patients had relapsed (87.5%), and 1 patient had died (12.5%). Conclusions: In our preliminary retrospective study, partially mismatched BMT with PTCy-based GVHD prophylaxis for advanced-stage CTCL was associated with minimal GvHD, no TRM, and good long-term survival. Investigation into relapse reduction is warranted.[Table: see text]
Feasibility of next generation sequencing (NGS) from Uzbekistan: A preliminary data analysis.
Authors: Zilola Avazovna Olimova, Dinesh Pendharkar
Journal: Journal of Clinical Oncology (2022)

e14579 Background: Molecular testing has become an important part of management of cancer patents. Due to local nonavailability and financial constrains NGS is picking up slowly in Uzbekistan. An attempt was being made to see feasibility and analyze next generation sequencing data from local population. Here we report data from first such big analysis. Methods: 76 advanced cancer patients were enrolled and tissue samples were sent for NGS. The analysis were sent to the lab for performing FOUNDATIONONE R CDx (F1CDx) - the NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations(indels), and copy numbers alterations(CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability(MSI), tumor mutational burden(TMB), and for selected forms of ovarian cancer, loss of heterozygosity(LOH) score, using DNA isolated from formalin-fixed, paraffin-embedded(FFPE) tumor tissue specimens. Results: Out of 76 patients (35 male 41female) there were 15/76 lung cancer patients, 13/76- breast cancer, 12/76 - colorectal, 5/76 - ovarian and other malignancies. In cohort of lung cancer, the multiple gene abnormalities detected were - EGFR-5/15; ALK-3/15; ROS-0; KRAS-1/15; NRAS-0; BRAF-1/15; MET-1/15; NTRK-3/15. In breast cancer population - BRCA1 mutation was found in - 3/13; BRCA2 in 1/13; ERBB-3/13; and ESR-1/13. In group with colorectal cancer the gene abnormalities located were - BRAF-1/12; KRAS-7/12: G12D-1; G12V-1; G12C-1; NRAS-0; MSI-3/7; MMR: MLH-1; MSH2-2; MSH3-2; MSH6-2. In ovarian cancer findings included - BRCA1 in 0/5; BRCA2-1/5; PALB-1/5; CHEK-1/5; PARP1-1/5. The most frequent genetic alteration observed in the whole group was TP53 (50/76). Commonest hereditary gene alterations besides TP53 were seen in ATM gene -12/76. A large number of Variant of Unknown Significance were also recorded. Conclusions: It is feasible to perform NGS analysis using reference laboratories. There is population of patients, willing to undergo specialized tests. Actionable molecular data information can be collected and utilized for patient care. No unique markers could be found due to small sample size.
A cross sectional study on female sexual function following pelvic radiotherapy.
Authors: Deepa Joseph, Pragya Singh, Bruzily Abraham, Sharanya Nair, Manoj Kumar Gupta
Journal: Journal of Clinical Oncology (2022)

e24051 Background: Pelvic radiotherapy (PRT) is an integral part of treatment in many pelvic cancers. PRT is associated with multiple organic changes in the genital area that have the potential to negatively impact female sexuality and quality of life. Fear of cancer transmission and stigma associated can result in lack of sexual activity and many women get abandoned by their partners. Often this topic is neglected and limited studies are available assessing female sexual function (FSF) especially from Indian subcontinent. This study was an attempt to assess the FSF in patients who had received PRT as part of their curative treatment for pelvic malignancy. Methods: This was an observational cross-sectional study conducted in January 2022. Study included female patients who received RT for pelvic malignancy. Patients with a minimum of 6 months follow up after RT with clinical complete response, sexually active before start of treatment &amp; living with their partners at time of study were included. Demographic profile was collected from treatment records. Socioeconomic status calculated using updated B J Prasad’s scale. Female Sexual Function Index (FSFI) questionnaire was used with score ≤ 26 indicating female sexual dysfunction (FSD). Questionnaire was filled by patients under supervision of a trained staff. 6 domains of sexual function i.e. desire, arousal, lubrication, orgasm satisfaction &amp; pain were studied. Patients reporting zero score in any of the domain indicating no sexual activity in the last 4 weeks were also included. Results: 38 eligible patients with age range from 34-69 years, mean age 51 years, 37% patients were &gt; 60 years. All were house wives, 40% illiterate, 50% high school &amp; below, 10% were above high school. 70% were from rural area. 13% belonged to upper class, 35% upper middle &amp; middle class, 52% to lower middle and lower class. Commonest diagnosis was carcinoma cervix (86%) followed by endometrium (10%) &amp; anorectum (4%). All patients with carcinoma cervix received radical chemoRT. Patients with Ca Endometrium were postoperative. 92% of all patients received pelvic EBRT &amp; 3% only vault brachytherapy. The mean duration from completion of RT was 17 months (range 6 – 41 months). FSD was found in 89%. Age wise mean scores in six domains of FSFI &amp; overall score is illustrated in the table. 0 score in at least one of the domain was reported by 65% patients. Conclusions: Study showed a very high incidence of FSD among pelvic cancer survivors after RT. Since there are limited data in this domain from Indian patients, this can become baseline data for further studies. Our data is limited by lack of comparison of FSD from age adjusted healthy females of this region.[Table: see text]
Adiposity in resectable colorectal cancer.
Authors: Jessica Hopkins, David Bigam, Vickie Baracos, Dean Eurich, Rebecca Reif, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2022)

3614 Background: Sarcopenia and myosteatosis affect survival in colorectal cancer (CRC). The role of adiposity is not yet fully elucidated. This study explores visceral and subcutaneous adipose tissue (VAT/SAT) distributions, and how they affect overall (OS), disease-free (DFS) and cancer specific survival (CSS). Methods: This retrospective cohort study, included resected stage I-III CRC in Alberta from January 2007 to December 2009. We excluded recurrent/metastatic disease or no CT scan. This study was approved by the Health Research Ethics Board at the University of Alberta. Body composition parameters were measured from CT scans. Sarcopenia and myosteatosis were defined by cohort-specific cut-off values. Total and visceral fat areas were indexed by height, and cohort-specific cut-offs defined total and visceral obesity (VO). SAT (SC:TFR) and VAT (V:TFR) to total adipose ratios were compared by gender, as described by Fleming. SAT and VAT fat radiodensity (Hounsfield units, HU) was measured and divided into quartiles. Differences between groups were compared with student’s t-test and Fisher Exact test. Cox proportional hazard models were created, adjusting for important covariates, to assess adiposity effects on OS, DFS and CSS. Results: Our cohort included 968 patients with a median follow up of 63.5 months. The majority were stage II (38.6%) and III (51.0%). In total, 67.9% had total obesity and 51.0% had visceral obesity. In males, there was no difference in the incidence of myosteatosis or sarcopenia, regardless of V:TFR or SC:TFR. In women, those with a high V:TFR or SC:TFR had significantly higher incidence of myosteatosis, but not sarcopenia. Men and women with elevated V:TFR had significantly lower VAT and SAT HU (p&lt;0.001, p=0.0113). Those with elevated SC:TFR had significantly higher VAT and SAT HU (p&lt;0.001). VAT and SAT HU was lowest in those with myosteatosis alone (p&lt;0.001; p=0.005). In survival analysis, VO and VAT HU quartiles predicted worse OS in uni-, but not multivariate analysis. SAT HU quartiles predicted worse survival in uni- and multivariate analysis, with the highest quartile of SAT HU predicting increased risk of death (HR 1.35, p=0.037). Adiposity was not predictive of CSS or DFS in uni- or multivariate analysis. Conclusions: This study demonstrated changes in VAT/SAT in relation to well described body composition parameters. SAT HU may have a more important role in OS than visceral adipose characteristics, despite known metabolic characteristics of VAT. True roles of adipose tissue in CRC outcomes remains unclear. VAT/SAT measurements using cross-sectional imaging allows for a detailed analysis and understanding of how adiposity may affect survival. [Table: see text]